Project Summary A considerable fraction of persons with depression also have elevated markers of inflammation but the precise relationship between the brain and immune system in health and disease remains unclear. Patients with depression and elevated inflammation respond less well to some common antidepressants, but may have better outcomes with others. This means there is potential to significantly improve outcomes of depression treatment through better understanding of the mechanisms linking the brain and immune system and how they may malfunction in inflammatory depression. One model suggests that a loss of homeostatic regulation of normal behavioral responses to inflammation (called sickness behavior) results in development of depression. Towards the long term goal of improving treatment of depression, we propose to test this theory using a detailed examination of the peripheral immune and behavioral responses to influenza vaccination. The immediate aim is to demonstrate the safety and feasibility of this experimental model in parsing differences in the behavioral immune response between depressed and healthy persons. Our work and that of others has shown that persons with depression and anxiety experience more change in mood than mentally healthy persons after receiving an influenza vaccine, and separately, that depression and psychosocial stress are associated with a more inflammatory immune response to influenza vaccine. In addition, influenza vaccine is a safe, universally recommended intervention, minimizing the risk to which participants will be exposed. Over five visits during two weeks we will examine the inflammatory response including mediators responsible for initiating and resolving inflammation, as well as the behavioral correlates to the immune response. We will also measure influenza antibodies prior to vaccination and at one month to determine whether participants mount a successful response to the vaccine. We predict that some depressed patients will weakly suppress the initial inflammatory response to vaccination and therefore experience a greater sickness response, including, for example, loss of interest and fatigue. We propose these subjects will make up a subgroup of patients who may benefit from immunotherapies for depression. By identifying differences in the response to vaccination over time, the results of this project will inform the efficient design and implementation of future projects capable of identifying inflammation induced changes in the brain as well as test treatments that specifically target the effects of inflammation on mood.